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. 2022 Nov 2;62(4):e48–e88. doi: 10.1093/rheumatology/keac551

Table 3.

Summary of maternal exposure to biological DMARDs and targeted synthetic DMARDs

Drug Studies (type and number) Pregnancy exposures (exposures per trimester) Foetal losses/total pregnancy outcomes Pregnancy duration and birth weight Malformations/total births Recommendation (GRADE/Strength of agreement)
TNFi (combined data for all licenced drugs) See individual drugs below, plus:

  • 7787

  • (1st ≥2929, 2nd/3rd ≥2150)

 886/4192 No significant adverse effect noted overall

  • 214/5157

  • Overall, no increase in rate of major malformations attributable to drug

  1. Women with no/low disease activity established on a tumour necrosis factor inhibitor (TNFi) with known placental transfer (INF, ADA, GOL) do not need to be switched to an alternative TNFi with established minimal placental transfer (CZP) either before or during pregnancy (GRADE 1B, SOA 100%)

  2. CZP is compatible with all three trimesters of pregnancy, has no to minimal placental transfer compared with other TNFi, and does not require any alteration to the infant vaccination schedule (GRADE 1B, SOA 100%)

  3. Women considered to have low risk of disease flare on withdrawal of TNFi in pregnancy could stop INF at 20 weeks, ADA and GOL at 28 weeks, and ETA at 32 weeks so that a full-term infant can have a normal vaccination schedule, with rotavirus vaccination at 8 weeks as per the UK schedule (GRADE 1B, SOA 99.5%)

  4. INF, ADA, ETA or GOL may be continued throughout pregnancy to maintain maternal disease control; in these circumstances, live vaccines should be avoided in infants until they are 6 months of age (GRADE 1B, SOA 100%)

  5. If a TNFi is stopped in pregnancy, it can be restarted as soon as practical post-partum in the absence of infections or surgical complications, regardless of breastfeeding status, to ensure control of maternal disease (GRADE 1C, SOA 100%)

  6. TNFi are compatible with breastmilk exposure (GRADE 1C, SOA 100%)
28 ct [277, 278, 295–298, 301–313, 315–323]
1 cs [279]
4 cc [172, 299, 300, 314]
CZP 2 ct [283, 284]

  • 567

  • (1st ≥371, 2nd/3rd ≥335)

 52/567 No significant adverse effect noted overall

  • 9/488

  • Overall, no increase in rate of major malformations attributable to drug

 See recommendations above
1 cs [285]
INF 9 ct [50, 260–263, 291–294]

  • 2645

  • (1st ≥1301, 2nd/3rd ≥92)

 255/2484 No significant adverse effect noted overall

  • 56/2090

  • Overall, no increase in rate of major malformations attributable to drug

 See recommendations above
ETA 5 ct [50, 52, 260, 286, 287]

  • 821

  • (1st ≥475, 2nd/3rd ≥207)

 73/383 No significant adverse effect noted overall

  • 47/676

  • Overall, no increase in rate of major malformations attributable to drug

 See recommendations above
3 cs [100, 266, 272]
4 cr [108, 109, 273, 274]
1 rct [288]
ADA 7 ct [50, 52, 252, 261, 280–282]

  • 473

  • (1st ≥425, 2nd/3rd ≥298)

 33/371 No significant adverse effect noted overall

  • 30/397

  • Overall, no increase in rate of major malformations attributable to drug

 See recommendations above
5 cs [99, 266, 268–270]
3 cr [271, 275, 276]
GOL 2 ct [289, 290]

  • 166

  • (NR)

 34/166 NR

  • 3/115

  • Overall, no increase in rate of major malformations attributable to drug

 See recommendations above
RTX 5 ct [50, 343, 344, 350, 354] 316 68/293 No significant adverse effect noted

  • 6/170

  • Overall, no increase in rate of major malformations attributable to drug

  1. Limited evidence has not shown RTX to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception (GRADE 2C, SOA 99.3%)

  2. RTX may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 99.7%)

  3. If RTX is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 98.7%)

  4. Based on limited evidence, maternal treatment with RTX is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
4 cs [345, 351–353] (1st ≥13, 2nd/3rd ≥1)
4 cr [346–349]
TOC 2 ct [358, 359] 365 84/354 No significant adverse effect attributable to drug (data limited by confounding)

  • 8/211

  • Overall, no increase in rate of major malformations attributable to drug

  1. Limited evidence has not shown IL-6i to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.7%)

  2. IL-6i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 100%)

  3. If IL-6i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 99.3%)

  4. Based on limited evidence, maternal treatment with IL-6i is compatible with breastmilk exposure (GRADE 2C, SOA 100%)
2 cs [356, 357] (1st ≥46, 2nd/3rd ≥2)
ANA 2 ct [50, 371] 48 3/43 No significant adverse effect attributable to drug

  • 2/41

  • (including one resulting in miscarriage at 30 weeks)

  1. Limited evidence has not shown IL-1i to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.8%)

  2. IL-1i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 100%)

  3. If IL-1i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 99.3%)

  4. Based on limited evidence, maternal treatment with IL-1i is compatible with breastmilk exposure (GRADE 2C, SOA 100%)
4 cs [367, 369, 370, 372] (1st ≥25, 2nd/3rd ≥40)
1 cr [368]
CAN 1 cs [369] 8
(all 1st)		 1/8 No significant adverse effect noted 0/7 See recommendations above
ABA 1 cs [175] 99 49/187 No significant adverse effect attributable to drug (data limited by confounding)

  • 10/104

  • Overall, no pattern of malformations attributable to drug

  1. Limited evidence has not shown ABA to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.3%)

  2. ABA may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 99.3%)

  3. If ABA is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 99.3%)

  4. Based on limited evidence, maternal treatment with ABA is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
1 cr [349] (1st ≥145, 2nd/3rd ≥10)
2 ct [375, 376]
BEL 1 ct [380] 66
(NR)		 18/66 No significant adverse effect attributable to drug (data limited by confounding)

  • 3/33

  • Overall, no pattern of malformations attributable to drug

  1. Limited evidence has not shown BEL to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.3%)

  2. BEL may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 99.5%)

  3. If BEL is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 98.8%)

  4. Based on limited evidence, maternal treatment with BEL is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
SEC 2 ct [387, 388] 244
(1st ≥161, 2nd/3rd NR)		 26/125 No significant adverse effect noted

  • 2/54

  • Overall, no pattern of malformations attributable to drug

  1. Limited evidence has not shown IL-17i to be teratogenic; however, there remains insufficient evidence to be confident that they are compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.3%)

  2. IL-17i may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 99%)

  3. If IL-17i are used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 99.3%)

  4. Based on limited evidence, maternal treatment with IL-17i is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
IXE 1 ct [389] 18
(NR)		 5/18 (spontaneous and induced) No significant adverse effect noted

  • 0/8

  • Overall, no pattern of malformations attributable to drug

 See recommendations above
UST 2 ct [391, 392] 517
(1st ≥31, 2nd/3rd ≥10)		 92/517 No significant adverse effect noted

  • 17/375

  • Overall, no pattern of malformations attributable to drug

  1. Limited evidence has not shown UST to be teratogenic; however, there remains insufficient evidence to be confident that it is compatible with pregnancy. Consider stopping the drug at conception. Any exposure, however, during pregnancy is unlikely to be harmful (GRADE 2C, SOA 99.3%)

  2. UST may be considered to manage severe maternal disease in pregnancy if no other pregnancy-compatible drugs are suitable (GRADE 2C, SOA 98.8%)

  3. If UST is used to treat severe maternal disease in the third trimester, it is currently recommended to avoid all live vaccines in the infant vaccination schedule until 6 months of age (GRADE 2C, SOA 99.3%)

  4. Based on limited evidence, maternal treatment with UST is compatible with breastmilk exposure (GRADE 2C, SOA 99.5%)
1 cs [393]
TOF 1 ct [397] 116
(all 1st, 2nd/3rd NR)		 15/72 No significant adverse effect noted

  • 2/44

  • Overall, no pattern of malformations attributable to drug

  1. There are insufficient data to make a recommendation on JAKi use during pregnancy and they should be stopped at least two weeks before planned conception (GRADE 2C, SOA 99.5%)

  2. There are insufficient data to recommend JAKi in breastfeeding and, given they are likely to transfer into breastmilk, they should be avoided (GRADE 2C, SOA 99.5%)

All studies that provided quantitative and/or qualitative information on the safety of the relevant drug in pregnancy were included; however, numerical outcome data could only be collated from papers where the relevant outcome was clearly quantified. Details of how numerical data in this table were derived are shown in Supplementary Data S3, available at Rheumatology online. 

ABA: abatacept; ADA: adalimumab; ANA: anakinra; BEL: belimumab; CAN: canakinumab; cc: case control; cr: case report; cs: case series; ct: cohort; CZP: certolizumab; ETA: etanercept; GOL: golimumab; IL-1i: IL-1 inhibitors; IL-6i: IL-6 inhibitors; IL-17i: IL-17 inhibitors; INF: infliximab; IXE: ixekizumab; JAKi: Janus kinase inhibitor; NR: not reported; rct: randomized controlled trial; RTX: rituximab; SEC: secukinumab; SOA: strength of agreement; TNFi: TNF-alpha inhibitor; TOC: tocilizumab; TOF: tofacitinib; UST: ustekinumab.